When the crosslinked hyaluronan gel is used as, for example, an anti-wrinkle injection, the crosslinked gel is required to have higher density and higher viscoelasticity for ensuring a certain volume in the injection portion. Also when the crosslinked hyaluronan gel is used as a controlled drug release preparation, in vivo retention for a long period of time is necessary for maintaining an adequate effect of the drug for a certain period of time. Therefore, a crosslinked hyaluronan gel having high density and high viscoelasticity is desirable.
Conventionally, the crosslinked hyaluronan gel has been prepared through a process including dissolving a solid hyaluronan in water, adding a crosslinking agent and an alkali thereto for a crosslinking reaction, and removing impurities (excess crosslinking agent and alkali) from the resulting hyaluronan gel (Patent Document 1).
However, since the hyaluronan has a high molecular weight, when it is dissolved in water, even if the concentration is low, the viscoelasticity of the aqueous solution is very high. Therefore, it takes significant time and effort to dissolve the hyaluronan in water in an industrial scale. In particular, when the concentration of a hyaluronan is increased for obtaining a crosslinked hyaluronan gel with high density, the viscosity of the liquid phase is significantly increased. Therefore, the processes of uniformly mixing the hyaluronan with a crosslinking agent and an alkali in an aqueous solution by stirring and of removing them by dialysis or the like are made very complicated. Thus, there has been a problem that large amounts of time and effort are necessary.
Furthermore, a crosslinked hyaluronan basically has high water swellability and viscoelasticity and thereby has problems that the handling thereof in storage, gel-preparation, or injection into a living body is difficult. Therefore, a crosslinked hyaluronan gel in a powder form that can be used as a desired gel by adding water at the point of use has been required. Furthermore, from the viewpoints of reducing the injection burden on a living body and allowing retention for a longer period of time in the living body, an approach to produce a crosslinked hyaluronan in a powder form and to directly inject the powder into a living body is also expected.
The crosslinked hyaluronan gel such as that disclosed in Patent Document 1 is produced by crosslinking a hyaluronan dissolved in water. Therefore, in order to obtain a crosslinked hyaluronan powder by such a conventional method, a crosslinked hyaluronan gel is produced, and then the gel is dried into a powder. However, the powder of the dried crosslinked hyaluronan gel released water without swelling, even if the water was added to the powder, and therefore the gel as that before being dried was not reproduced.
In addition, Patent Document 2 discloses a powder obtained by crosslinking a hyaluronan in a water-acetone liquid mixture, followed by heating for drying. However, the crosslinked hyaluronan powder obtained by this method is also poor in practical utility as a gel, because of its significantly low swellability in water to form approximately a viscous liquid state.
Patent Document 1: Japanese Patent No. 3094074
Patent Document 2: Japanese Unexamined Patent publication No. 60-130601